Invited
NOVEL CANCER MODELS-BASED IDENTIFICATION OF TARGETS FOR THE RATIONAL DESIGN OF PRECISION NANOMEDICINES

Tumor progression is dependent on a number of sequential steps, including initial tumor-vascular interactions and recruitment of blood vessels (i.e., the “angiogenic switch”), as well as an established interaction of tumor cells with their surrounding microenvironment and its different immune, endothelial and connective cellular and extra-cellular components. Failure of a microscopic tumor, either primary, recurrent or metastatic, to complete one or more of these early stages may lead to delayed clinical manifestation of the cancer (i.e., tumor dormancy). Micrometastasis, dormant tumors, and residual tumor cells – referred to as minimal residual disease, contribute to the occurrence of relapse, and constitute fundamental clinical manifestations of tumor dormancy that together are responsible for the vast majority of cancer deaths. However, although the tumor dormancy phenomenon has critical implications for early detection and treatment of cancer, it is one of the most neglected areas in cancer research and the associated biological mechanisms are still mostly unknown.

We have created several models of patient-derived xenografts mimicking pairs of dormant vs fast-growing, primary vs metastatic and drug-sensitive vs resistant cancers. We investigated the molecular and cellular changes in tumor-host interactions that govern tumor dormancy. Those led to the discovery of novel targets and provided important tools for cancer theranostics. Based on the acquired knowledge, we designed a new strategy to improve treatment outcomes of patients with bone neoplasms, glioblastoma, brain metastases, melanoma, breast and prostate cancers. We have identified molecular signatures that, following selective delivery into their target cells, can potentially induce a dormant-like phenotype. This goal was achieved by rational design of a library of polymeric precision nanomedicines guided by high resolution, intravital non-invasive imaging techniques.